AU675119B2

AU675119B2 - Use of lamotrigine for treating AIDS-related neural disorders

Info

Publication number: AU675119B2
Application number: AU61439/94A
Authority: AU
Inventors: Anne Bousseau; Adam Doble; Erik Louvel
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1993-03-05
Filing date: 1994-02-25
Publication date: 1997-01-23
Anticipated expiration: 2014-02-25
Also published as: SK107495A3; IL108844A; JPH08507509A; US5629312A; NO953370D0; SK107695A3; CZ226195A3; NO953371L; AU675118B2; ATE201597T1; ZA941530B; HU217132B; HU9502583D0; IL108846A0; PT687176E; RU2157205C2; AU6143794A; FR2702148B1; JPH08507508A; ATE147981T1

Abstract

The invention relates to the application of riluzole or the pharmaceutically acceptable salts of this compound in the treatment of neuro-AIDS.

Description

Q;\01' 1 )11 14 i 43.3U .3 181.1 S APPLICATION OF LAMOTRIGINE IN THE TREATMENT OF NEURO-AIDS Thc present invention relates to a novel therapeutic application of lamotrigine or the pharmaceutically acceptable salts of this compound.

Lamotrigine or the pharmaceutically acceptable salts of this compound are described as anticonvulsants and antiepileptics, in particular in Patent EP 247,892.

It has now been found, surprisingly, that this compound may also be used in the treatment of neuro-AIDS.

S 10 Accordingly, the invention provides a method of treatment of neuro-AIDS which comprises administering to a patient in need thereof an effective amount of lamotrigine or a pharmaceutically acceptable salt thereof.

The term neuro-AIDS includes disorders involving dementia, cognitive disorders, 0 neuropathies, myopathies, ocular disorders and all neurological symptoms associated with the 15 HIV-1 virus.

The activity of lamotrigine in neuro-AIDS was demonstrated in the test of neuronal death induced by the GP-120 protein, an envelope protein of the HIV-1 virus, according to the following protocol: Cortical cell cultures are prepared according to the method described by SINDOU et al., Brian Res., 572, 242-246 (1992). After 8 to 10 days of culture, neurons which have acquired a correct neuritic shape are used for the tests. The cells are kept at 37"C in a CO, incubator for the whole of the experiment.

/0 W:OIMiRW)iU 439'04,323. I)I19 IlA- Neuronal sur-vival is assessed before application and after 24 hours of application of the test produced by a colorimetric technique using Tuspan

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2 Blue, counting predetermined fields (semi-quantitative method). A minimum of 4 culture dishes per concentration (100 neurons per dish) were analysed.

In a first series, neuronal survival of the culture medium was determined without any product.

Neuronal survival is then approximately 87 In a second series, the toxicity of the GP120 in culture was demonstrated. The GP120 was applied alone to the culture medium for 24 hours at a concentration of 20 pmol, and brings about a neuronal death which is of the order of 43 In the third series, the test product dissolved in dimethyl sulphoxide (10 3 M) is applied 5 minutes before the application of GP120 and thereafter incubated for 24 hours at concentrations from 10 7 to 10-8 mol. Neuronal survival is greater than 80 As pharmaceutically acceptable salts, there may be mentioned, in particular, the addition salts with inorganic acids, such as hydrochloride, sulphate, nitrate or phosphate, or organic acids, such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulphonate, isethionate, theophyllineacetate, salicylate, phenolphthalinate, methylenebis (j-hydroxynaphthoate) or substitution derivatives of these derivatives.

The medicinal products consist at least of lamotrigine, in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active.

The medicinal products according to the invention may be employed orally or parenterally.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, wafer capsules) or granules may be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (drag6es) or a varnish.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs, containing inert diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin, may be used. These compovitions can comprise substances other than diluents, for example wetting, sweetening, thickening, flavouring or stabilizing products.

The sterile compositions for parenteral administration can preferably be suspensions, emulsions or aqueous or non-aqueous solutions. As a solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents may be employed. These compositions can also contain adjuvants, especially wetting agents, tonicity agents, emulsifiers, dispersants and stabilizing agents. The sterilization may be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The doses depend on the effect sought, the treatment period and the administration route used; they are generally between 50 and 400 mg per day orally for an adult, with single doses ranging from 25 to 200 mg of active substance.

Generally speaking, the doctor will determine the appropriate dosage in accordance with the age and weight and all other factors distinctive to the subject who is to be treated.

The examples which follow illustrate some medicinal products according to the invention: Example A Tablets containing a 50 mg dose of active product and having the following composition are prepared according to the usual technique: Active product 50 mg Mannitol 64 mg Microcrystalline cellulose 50 mg Povidone excipient 12 mg Carboxymethylstarch sodium 16 mg Talc 4 mg Magnesium stearate. .2 mg Colloidal silica, anhydrous .2 mg Mixture of methylhydroxypropylcellulose, polyethylene glycol 6000 and titanium dioxide (72:3.5:24.5) q.s. 1 finished film-coated tablet weighing 245 mg Example B Hard gelatin capsules containing a 50 mg dose of active product and having the following composition are prepared according to the usual technique: Active product 50 mg Cellulose 18 mg Lactose 55 mg Colloidal silica 1 mg Carboxymethylstarch sodium 10 mg Talc 10 mg Magnesium stearate .1 mg Example C An injectable solution containing 10 mg of active product and having the following composition is prepared:

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Q:\01'l131MIM61439494,323 1811196 -6- Active product 10 mg Benzoic 80 m g Benzyl 0.06 cm 3 Sodium 80 mg Ethanol, 95 0.4 cm Sodium 24 mg Propylene 1.6 cm 3 W q.s. 4 cm 10 The invention also relates to the process for preparing medicinal products which are useful in the treatment of neuro-AIDS, consisting in mixing lamotrigine or the pharmaceutically acceptable salts of this compound with one or more compatible and o :pharmaceutically acceptable diluents and/or adjuvants.

Throughout this specification and claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Claims

1. A method of treatment of neuro-AIDS, which comprises administering to a patient in need thereof an effective amount of lamotrigine or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1, for the treatment of disorders involving dementia, cognitive disorders, neuropathies, myopathy, ocular disorders and all neurological symptoms associated with the HIV-1 virus. a

3. A method according to claim 1 or 2, which comprises administering from 25 to 200 mg of lamotrigine. 10

4. Lamotrigine or a pharmaceutically acceptable salt thereof when used in the treatment .of neuro-AIDS. DATED this 18th day of November, 1996 Rhone-Poulenc Rorer S.A. o* DAVIES COLLISON CAVE Patent Attorneys for the Applicant INTERNATIONAL SEARCHl REPORT Inter, hal Application No PCT/FR 94/00210 A. CLASSIFICATION OF SUBJECT MATTER IPC 5 A61K31/53 According to International Patent Classification (IPC) or to both national clasification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by claslicauion symbols) IPC 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of :cument, with indication, where appropil of the relevant passages Relevant to claim No. X EP,A,O 247 892 (THE WELLCOME FOUNDATT)N 4 LIMITED) 2 December 1987 cited in the application Y see the whole document 1-3 Y ANNUAL MEETING OF THE AMERICAN EPILEPSY 1-3 SOCIETY, BOSTON, MASSACHUSETTS, USA, DECEMBER,, VOL. 30, NO.

5, PAGE(S) 662, 1989 SUSSMAN L D-P et al 'DRAMATIC RESPONSE TO LAMOTRIGINE IN TWO PATIENTS WITH NEUROLOGIC DEFICITS SECONDARY TO FREQUENT INTRACTABLE SEIZURES' see the whole document Further documents are listed in the continuation of box C. Patent family members are listed in annex. Special categories of cited documents Spal categories of ted documents later document published after the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on o after the international X' document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority clam(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another Y' document of particular relevance; the claimed invention citation or other speaal reason (as specified) cannot be considered to involve an inventive step when the document referring tt an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art later than the prority date claimed document membei of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 26 May 1994 ij l Name and mailing address of the ISA Authonzed officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 340-2040, Tx. 31 651 cpo n, Krautbauer, B Fam 31.70) 340-3016 Form PCT/ISA/210 (second sheet) (July 1992) page 1 of 2 INTERNATIONAL SEARCH REPORT ln er Al Acppiauon No PCT/FR 94/00210 C.(Continuaton) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropnate, of the relevant pasagcs Relevant to claim No. Y MEETING OF THE BRITISH PHARMACOLOGICAL 1-3 SOCIETY, LONDON, ENGLAND, UK, SEPTEMBER,, VOL. 107 (PROC. SUPPL. DEC., PAGF(S) 337P, 1992 NAKAMURA-CRAIG M et al 'ANALGESIC EFFECTS OF LAMOTRIGINE IN AN EXPERIMENTAL MODEL OF NEUROPATHIC PAIN IN RATS' see the whole document Y DTSCH MED WOCHENSCHR (GERMANY, WEST), DEC 1-3 16 1988, VOL. 113, NO. 50, PAGE(S)

1975-81, Hartung HP et al 'Neuromuskulare Manifestationen der HIV-1- und HTLV-I-Infektionen.' see the whole document Y ANNUAL MEETING OF THE AMERICAN EPILEPSY 1-3 SOCIETY, SEATTLE, WASHINGTON, USA, DECEMBER,, VOL. 33, SUPPL. 3, PAGE(S) 69, 1992 KOPPEL B et al 'ANTIEPILEPTIC DRUG TREATMENT IN PATIENTS WITH AIDS' see the whole document Y CIRR. OPIN. NEUROL. NEUROSURG. 1-3 vol. 5, no. 4 1992 pages 508 513 B.S. MELDRUM ET AL. 'Excitatory amino acid receptors and disease' see the whole document Y ARCH. NEUROL. 1-3 vol. 48, no. 12 1991 pages 1281 1284 KIEBURTZ ET AL. 'Excitotoxicity and dopaminergic dysfunction in the Acquired Immunodeficiency Syndrome Dementia Complex' see the whole document Form PCT/ISA/310 (cntinuation of second sheet) (July 1992) page 2 of 2 INTERNATIONAL SEARCH REPORT Informiation on patent family members Inter. nal Application No PCT/FR 94/00210 Patent document I Publication IPatent family I Publication cited in search report _]date I member(s) date EP-A-0247892 02- 12-87 AU-B- 597982 AU-A- 7368487 Fl-C- 90770 JP-A- 62289570 US-A- 4847249 14-06-90 03-1P-'-87 25-03-94 16- 12-87 11-07-89 Form PCT/ISA/31O (patnt family annex) (July 1992) I(AITOI(l 10 10411111W11V INVPIMAIIONAI K llGT/l 11 94/00,110 A Yf A iIf v N 11! 1 01111 0)11 I.A D II1vANJ01 CIB 5 A61K31/S3 Scion la classification internationaic des brevets (CIB) ou Alan fois seion Is classification nainl e.t la, CI B3. DOMAINFf SUR LESQUELS LA RECHERCHE A PORTE Documentation mi ismale consulte (systeme de clasmiication suivs des syrnboles de classement) CIB 5 A61K Documentaion consuitte autre que Is documentation rninmmaie danm la mesure ou ces documents rel~vent des domasnes sur lesquels a portt la recherche Base dc donnees 6lectronique consulthe au cours de ia recherche intemnationale (nom de Is base de donntes, et si cela est rtalisable, terenes de recherche utihis) C. DOCUMENTS CONSIDERES COMME PERTINENT'S Cattgone' Identification des documents cit~s, avec, Ic cas echeant, l'indication des passages pertinents no. des revendications vistsA X EP,A,O 247 892 (THE WELLCOME FOUNDATION 4 LIMITED) 2 Decembre 1987 cI t6 dans la demande Y voir le document en entier 1-3 Y ANNUAL MEETING OF THE AMERICAN EPILEPSY 1-3 SOCIETY, BOSTON, MASSACHUSETTS, USA, DECEMBER,, VOL. 30, NO. 5, PAGE(S) 662, 1989 SUSSMAN L D-P et al 'DRAMATIC RESPONISE TO LAMOTRIGINE IN TWO PATIENTS WITH NEUROLOGIC DEFICITS SECONDARY TO FREQUENT INTRACTABLE SEIZURES' voir le document en entier EE Voir Ia suite du cadre C pour la fin die I& luste des documents [J Les documents de failes de brevets; sont ineliquts en annexe *Cattgones sptcales de documnents Ct document ultericur publit aprts la date de dtpat international ou la date de priarith et n'appartenenant pas A I'etat de la document defissant U~ktat genetral de la technique, non technique pertinent, rnais cite pur coinpreneire Ic prmncipe onsid~r6 comme particuittrement pertinent ou Ia titeeconstituntIa base de l'invention document anttneur, mass publit A In date dce dtp~t interratiosnal W ouetnriuirmn etnnt 'neto eedqe epu ou ap#.st et.e date dtecns~e am nouv ~lleicme n L' niqu tne c tiv g*rnnt docmen nouan ele un doute sur= unequnt revndiation d W pounewole pour deter nin d ate d e pubelication d'ue inventive par rapport au document consid~rt isoltment prione cit6no pour dttner a dpae dle ublcain due document particulierement pertinent; I'invention revenduc autre n peutio oupu n asnseiae(cl uidqttire considertc comnme impliquant usne activittinetive '0 document se reftrant A tine divulgation orale, A un wage, A loqe I document est associt A tin oil plusieurs autres une cxposxtion ou tows autres moyens documents de meme nature, cette combinaison Clarit tvidente Pdocument publit a'vant I a date de depot international, mai pour une personne du meter postenecurement A la date de prionte revendiqiuc W& document qui fait partie de la meme famnille de brevets Datt: A Iaquelie I a rceherche intemnationale a 6tt effectivement achaee Date d'exptdition du present rapport de recherche intemtationace 26 Mai 1994 14. 06. 94 Nom et aetresse postile de I'adnunistration chargtc de la recherche internatiorale Fonctionnaire autorsC CAice Europten des Brevets, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk TJ. (+31-70) 340-2040, Tx. 31 651 epo nl,Kru aer B Faxc 31.70) 340-3016 rub e ,B Fom sAur PCT/ISA/211 (dauxiama touille) (juiliet 19921 page 1 de 2 RA,4'00' 1t, 10,0104111 IN'll.0N'11NA11 PCT/FR 94/00210 C(suite) DOCUMEiNTS CONSIDIRS COMMII P1lIVIIINWS Catkoii tdentification des documents citts, avcc, le cas tchtant, I'indiczuon des pa~ages pertjnents no. des revcndicntuons vias Y MEETING OF THE BRITISH PHARMACOLOGICAL 1-3 SOCIETY, LONDON, ENGLAND, UK, SEPTEMBER,, VOL. 107 (PROC. SUPPL. DEC., PAGE(S) 337P, 1992 NAKAMURA-CRAIG M et al 'ANALGESIC EFFECTS OF LAMOTRIGINE IN AN EXPERIMENTAL MODEL OF NEUROPATHIC PAIN IN RATS' voir le document en entier Y DTSCH MED WOCHENSCHR (GERMANY, WEST), DEC 1-3 16 1988, VOL. 113, NO. 50, PAGE(S) 1975-81, Hartung HP et al 'Neuromuskulare Manifestationen der HIV-1- und HTLV-I-Infektionen.' voir le document en entier Y ANNUAL MEETING OF THE AMERICAN EPILEPSY 1-3 SOCIETY, SEATTLE, WASHINGTON, USA, DECEMBER, VOL. 33, SUPPL. 3, PAGE(S) 69, 1992 KOPPEL B et al 'ANTIEPILEPTIC DRUG TREATMENT IN PATIENTS WITH AIDS' voir le document en entier Y CURR. OPIN. NEUROL. NEUROSURG. 1-3 vol. 5, no. 4 1992 pages 508 513 B.S. MELDRUM ET AL. 'Excitatory amino acid receptors and disease' voir le document en entier Y ARCH. NEUROL. 1-3 vol. 48, no. 12 1991 pages 1281 1284 KIEBURTZ ET AL. 'Excitotoxicity and dopaminergic dysfunction in the Acquired Immunodeficiency Syndrome Dementia Complex' voir le document en entier Foffnuizire PCTIISA/210 (suite deI& deuime feuilhn) (juiliet 1992) page 2. de 2 RAPPO'' DEI RI'(C-WW t iA NTiI:NAIONA I JX Ifi~llngti No Ronoi~gnc~q oItJ( AU mor~b~ o (rniic'doPCT/FR 94/00210 Document brevet cit6 Date de M mrs)dlaDate dc au rapport de recherche pubfication fmledbrees) e Iatio EP-A-0247892 02-12-87 AU-B- 597982 14-06-90 AU-A- 7368487 03-12-87 Fl-C- 90770 25-03-94 ~JP-A- 62289570 16-12-87 US-A- 4847249 11-07-89 Formwalre PCT/ISA/210 (mnnexe farmilis do brevetz) (juillet 1992)